Topical formulations for treating neuropathy

ABSTRACT

Compositions for the topical or transdermal treatment of neuropathy. More particularly, transdermal or topical compositions including a combination of ingredients that provide a surprising degree of effective relief from the symptoms of peripheral neuropathy are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/749,183, filed Mar. 29, 2010, now U.S. Pat. No. 8,137,711 issued onMar. 20, 2012, which is a continuation of U.S. application Ser. No.10/307,509, filed Nov. 25, 2002, now U.S. Pat. No. 7,687,080, issuedMar. 30, 2010. The disclosures of the above applications and patents arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and compositions for thetopical treatment of neuropathy. More particularly, the presentinvention relates to transdermal compositions including a combination ofingredients that provide a surprising degree of effective relief fromthe symptoms of neuropathy and to methods for administering topicalcompositions to treat neuropathy.

2. Description of the Prior Art

Peripheral neuropathy is a condition involving nerve-end damage anywherein the body. Peripheral neuropathy generally refers to a disorder thataffects the peripheral nerves, most often manifested as one or acombination of motor, sensory, sensorimotor, or autonomic neuraldysfunction. The wide variety of morphologies exhibited by peripheralneuropathies can each be uniquely attributed to an equally wide varietyof causes. For instance, peripheral neuropathies can be geneticallyacquired, can result from a systemic disease, can manifest as apost-surgical complication, or can be induced by a toxic agent. Sometoxic agents that cause neurotoxicities are therapeutic drugs,antineoplastic agents, contaminants in foods or medicinals, andenvironmental and industrial pollutants.

Neuropathy is a major complication of diabetes mellitus. Nowell-established treatments exist for either its symptomatic treatmentor for prevention of progressive decline in nerve function. Estimates ofthe prevalence of neuropathy in diabetes vary widely, from a low of 5%to a high of 80%, largely due to the numerous definitions and clinicaldescriptions of neuropathy. Nevertheless, the additive effects ofneuropathy in the suffering diabetic patient are well known anddocumented. The effect of the neuropathy is complex. The loss of sensoryinformation from the foot is related to abnormal and prolonged pressureon the areas of the foot (sensory neuropathy). Motor neuropathy leads todeformity, further increasing pressure loading on the foot. In autonomicneuropathy, loss of innervation of the sweat glands results in dry skinthat cracks creating an environment amenable to infection. Autonomicdysfunction contributes further by altering the distribution ofmicro-circulatory blood flow, directing the blood flow through shuntsand away from the nutritive skin capillaries. These factors as a whole,in conjunction with foot trauma, result in skin breakdown and ulcers.

Scientists have not yet determined the mechanism that leads to nervedamage in diabetes, but it is believed to be multifactorial. Thesefactors include genetic predisposition, metabolic and vascularabnormalities, and lack of perturbation of growth factors. The responseof the peripheral nervous system to the metabolic effects of diabetesdoes not appear to differ between type 1 and type 2 diabetes, whichsuggests a likelihood of similar clinical response to therapies in thetwo primary forms of the disease. There seem to be a number ofsusceptibility factors, as yet unknown, for the development ofneuropathy, which operate in the presence of hyperglycemia (high bloodsugar).

Although a number of neuropathies are related to the disease diabetesmellitus, others, although not known to be related to diabetes aresimilar in their physiological effects on the peripheral vascularsystem. Such diseases include Raynaud's Phenomenon, including CRESTsyndrome, autoimmune diseases such as erythromatosis, and rheumatoiddiseases. Other peripheral neuropathies include the following: HIVassociated neuropathy; B₁₂-deficiency associated neuropathy; cranialnerve palsies; drug-induced neuropathy; industrial neuropathy;lymphomatous neuropathy; myelomatous neuropathy; multi-focal motorneuropathy; chronic idiopathic sensory neuropathy; carcinomatousneuropathy; acute pain autonomic neuropathy; alcoholic neuropathy;compressive neuropathy; vasculitic/ischaemic neuropathy; mono- andpoly-neuropathies.

For example, among the most important toxic agents causing peripheralneuropathy are therapeutic agents, particularly those used for thetreatment of neoplastic disease. In certain cases, peripheral neuropathyis a major complication of cancer treatment and is the main factorlimiting the dosage of chemotherapeutic agents that can be administeredto a patient (Macdonald, Neurologic Clinics 9:955-967 (1991)). This istrue for the commonly administered agents cisplatin, paclitaxel andvincristine (Broun, et al., Am. J. Clin. Oncol. 16:18-21 (1993);Macdonald, Neurologic Clinics 9:955-967 (1991); Casey, et al., Brain96:69-86 (1973)). The identification of methods for preventing oralleviating dose-limiting peripheral neuropathologic side effects wouldallow higher, and more therapeutically effective doses of thesechemotherapeutics to be administered to patients, i.e., the therapeuticefficacy of such chemotherapeutics is typically a function of dose andtherefore, increasing dosage provides increased patient survival(Macdonald, Neurologic Clinics 9:955-967 (1991); Oxols, Seminars inOncology 16, suppl. 6:22-30 (1989)).

Tragically there is no existing method for adequately, predictably andspecifically treating established neuropathic pain (Woolf C. et al.,Neuropathic Pain: Aetiology, Symptoms, Mechanisms, and Management,Lancet 1999; 353: 1959-64). Present treatment methods for neuropathicpain consists of merely trying to help the patient cope throughpsychological or occupational therapy, rather than by reducing oreliminating the pain experienced.

Currently, there are a limited number of drugs available for thetreatment of neuropathy. Most treatments composition and methods aredirected towards relief of pain. Currently, there are several categoriesof treatments utilized, including medical procedures and drugs, whichare provided locally or systemically. For example, current methods totreat neuropathic pain include administration of local anesthetic blockstargeted to trigger points, peripheral nerves, plexi, dorsal roots, andto the sympathetic nervous system. However, these treatments have onlyshort-lived antinociceptive effects. Additionally, longer lastinganalgesic treatment methods, such as blocks by phenol injection orcryotherapy raise a considerable risk of irreversible functionalimpairment. Furthermore, chronic epidural or intrathecal (collectivelycalled “intraspinal”) administration of drugs such as steroids, opioidsor midazolam have significant side effects and questionable efficacy.Medical procedures are ineffective and often expensive, leading tovarious pains that many times supercede the original pain.

The current standard of practice for the non-invasive treatment of thevarious neuropathies include the following drug classes: (1) TheNon-Steroidal Anti-inflammatory Drugs (NSAIDs); (2) Narcotic analgesics;(3) Tricyclic antidepressants; and (4) Anticonvulsants, e.g.,carbamazepine and gabapentin. These classes are available commerciallyas oral products and, generally, are administered via the oral route.Because they are distributed systemically throughout the body, theirvarious side effects limit their effectiveness. The NSAIDs, for example,when taken orally cause gastric distress—including ulcers. The otherthree classes share other common side effects, including drowsiness,dizziness, disorientation, and gastrointestinal upset to name but a few.

Several topical agents (creams, ointments, liniments and the like) havebeen utilized for the relief of the pains and aches of neuropathies.Most of these have provided a little, but only temporary, relief topersons suffering from pain. Many combinations of varying ointments,creams, aqueous solutions, liniments and the like for the treatment ofneuropathies have been employed. The most efficacious of these containsas its active ingredient the vegetable products derived from the seedand pods of the capsicum plant, commonly known as red pepper.Capsicum-derived ointment is devised for external application to theaffected area of the body by applying to the area adjacent to themuscle, joint or tendon and rubbing it into the skin. The activeingredient is capsaicin. With initial as well as persistent application,capsaicin is effective to relieve the aches and pains of various muscleor skeletal origin, such as arthritis, muscle strains, tendonitis,bursitis and soft tissue diseases.

U.S. Pat. No. 5,665,360 (Mann) relates to the treatment of peripheralneuropathies associated with diabetes mellitus by periodic topicalapplication of a composition containing capsaicin as the activeingredient. When applied to the skin of the affected area, pain andburning associated with the neuropathy are said to be reduced. However,capsaicin has been shown to kill nerve endings in some cases and isextremely irritating to the dermis. Thus this composition suffers fromthese disadvantages.

The use of ketamine transdermally in an organogel has shown some promisein the treatment of neuropathy. Ketamine is an N-methyl-D-aspartatereceptor antagonist and thus blocks a cascade of intracellular eventsthat inhibit the hyper excitability of spinal cord neurons. Animal datashow that certain spontaneous pains and allodynia have been treatedsuccessfully with Ketamine. Also, in humans, phantom limb pain has beentreated with success (Nadine & Bouhassira, Acta. Neurol. Scand 1999(Supp 173):12-24). Ketamine has been used experimentally to treatneuropathic pain by a variety of routes including the intravenous andsubcutaneous. The topical form of Ketamine is effective in treatingpainful neuropathy when other traditional medicines have failed.(Crowley et al., International Journal of Pharmaceutical Compounding1998; 2:122-1273).

Other compositions have been employed, including combinations ofindividual compounds. U.S. Pat. No. 6,387,957 B1 (Frome) relates to thetreatment of Sympathetically Mediated Pain (SMP), which include variousneuropathies, employing the compounds ketamine (NMDA receptorantagonist), amitriptyline (anticholinergic antidepressant), andguanethidine (sympathetic blocking agent), in combination orindependently. However, the compounds employed by Frome actindependently of each other as illustrated by the effectiveness ofindividual compounds. Frome's invention lacks any synergism of thecompounds as the compounds merely complement the other compounds, butdoes not synergize, or supplement, the activities of the othercompounds. For example, ketamine a very potent antineuropathic agent wasused in limited concentrations. Whether alone or in combination, smallconcentrations of ketamine were likely used due to ketamine's knownneurotoxic effects. Frome's invention also suffers from limitations inthe preparation, dosage, application or administration methods andpotential side effects. The effectiveness of Frome's compounds dependson the volume of the preparation and whether the compounds are alone orin combination. The side effects of amitriptyline and guanethidine arewell known. These are disruptive to a person's quality of life and arenot addressed by Frome in his patent.

Accordingly, there remains a need in the art for effective treatmentsfor neuropathies, and other neuropathic pains.

SUMMARY OF THE INVENTION

In a one aspect, the compositions described herein can provide for thetreatment of peripheral neuropathy, and can include a therapeuticallyeffective amount of ketamine, gabapentin and clonidine in apharmaceutically acceptable diluent or carrier suitable for topical ortransdermal use.

An additional ingredient can be added as needed to increase theanalgesic effectiveness of the combination of ketamine, gabapentin, andclonidine. Specifically, topical compositions can include an additionalingredient that increases absorption and/or penetration of thecombination of ketamine, gabapenitn and clonidine.

The topical compositions described herein can also include an additionalingredient selected from the group consisting of: NMDA ligands, AMPAligands, non-NMDA or AMPA ligands, TNF-1α ligand, GABA ligand and α-2ligands. Additional ingredients can also be an analgesic.

In further embodiments, the additional ingredient can be selected fromthe group consisting of: capsaicin, lidocaine, bupivacaine, mepivacaine,ropivacaine, tetracaine, etidocaine, chloroprocaine, prilocaine,procaine, benzocaine, dibucaine, dyclonine hydrochloride, pramoxinehydrochloride, benzocaine, and proparacaine. The following can also bean additional ingredient: amitriptyline, baclofen, loperamide,nifedipine, pentoxifylline.

In an alternative embodiment of the compositions described herein, ananalgesic which can potentiate the activity of ketamine could be admixedwith ketamine and gabapentinin synergistic topical compositions. In oneembodiment, the analgesic is clonidine. Suitable pharmaceuticallyacceptable carriers and/or diluents include conventional orunconventional solvents, dispersion media, fillers, aqueous solutions,antibacterial and anti-fungal agents, absorption-promoting agents, andthe like.

Except insofar as any conventional medium or agent is incompatible withthe active ingredients, use thereof in the pharmaceutical compositionsdescribed herein is contemplated. Supplementary active ingredients canalso be incorporated into the compositions. For example, the topicalcomposition may additionally include a Substance P blocking agent, aMu-agonist, a non-NMDA calcium channel antagonist, or a TNF-1αantagonist.

The transdermal preparations described herein include any formulationssuitable for topical application, and include: aqueous creams,ointments, gels, lotions, roll-on liquids, sprays, glass bead wounddressings, and synthetic polymer dressings impregnated with thecompositions described herein. These preparations may also includecompounds, such as dimethylsulfoxime, which would facilitate the passageof the active ingredients across the skin keratin barrier and into theepidermis. Preferably the preparation is a cream. Other formulations thecompositions can be incorporated into include oils, suppositories,foams, liniments, aerosols, buccals, and sublingual tablets ortransdermal devices for absorption through the skin or mucous membranes.

In other aspects, methods described herein are directed to treatingperipheral neuropathy, comprising the step of transdermal or topicaladministration of an effective amount of a pharmaceutical composition ofketamine, gabapentin and clonidine to the affected area of a subject inneed of such treatment. Other drugs or ingredients may be added asneeded to increase the analgesic effect.

In preferred embodiments, the peripheral neuropathy is a diabeticneuropathy. It will be clearly understood that the diabetic neuropathymay be associated with Type 1 (insulin-dependent) diabetes, Type 2(non-insulin-dependent) diabetes, or both.

In other preferred embodiments, the neuropathy is a non-diabeticneuropathy. Such a non-diabetic neuropathy may be genetically acquired,such as Charcot-Marie-Tooth syndrome. In other embodiments theperipheral neuropathy can result from a systemic or infectious diseasesuch as HIV, or an infectious disease condition such as AIDS. In furtherembodiments, the peripheral neuropathy manifests as a post surgicalcomplication.

In other embodiments the peripheral neuropathy is induced by a toxicagent. For example, the peripheral neuropathy can be caused by achemotherapeutic agent such as taxol, vincristine, cisplatin, an agentused for the treatment of an infectious diseases such as streptomycin,didanosine or zalcitabine, or any other chemically toxic agent.Infectious disease conditions such as post-polio syndrome orAIDS-associated neuropathy are specifically contemplated.

Other peripheral neuropathies include the following: HIV associatedneuropathy; B₁₂-deficiency associated neuropathy; cranial nerve palsies;drug-induced neuropathy; industrial neuropathy; lymphomatous neuropathy;myelomatous neuropathy; multi-focal motor neuropathy; chronic idiopathicsensory neuropathy; carcinomatous neuropathy; acute pan autonomicneuropathy; alcoholic neuropathy; compressive neuropathy;vasculitic/ischaemic neuropathy; mono- and poly- neuropathies.

In further embodiments, the neuropathy is due to low back pain,Guillain-Barre Syndrome, or sciatica.

Further embodiments include methods for treating a subject sufferingfrom peripheral neuropathy, the methods comprising topicallyadministering an effective amount of a composition comprising ketamine,gabapentin and a third analgesic which potentiates the activity ofketamine, formulated in a pharmaceutically acceptable topical carrier.

Other embodiments include methods for treating a subject suffering fromneuropathic pains, the method comprising topically administering aneffective amount of a composition comprising ketamine, gabapentin andclonidine, formulated in a pharmaceutically acceptable carrier fortopical treatment.

The compositions described herein can be administered in therapeuticallyeffective amounts. A therapeutically effective amount means the amountrequired to at least partly to attain the desired effect, i.e., toalleviate or prevent the symptoms of the peripheral neuropathy.

Such amounts will depend, of course, on the particular condition beingtreated, the severity of the condition, and individual patientparameters. These include age, physical condition, size, weight andother concurrent treatment. The amounts prescribed will be at thediscretion of the attending physician. These factors are well known tothose of ordinary skill in the art, and can be addressed with no morethan routine experimentation. It is generally preferred that a minimumeffective dose be determined according to sound medical judgment. Itwill be understood by those of ordinary skill in the art, however, thata higher dose may be administered for medical, psychological or otherreasons.

The compositions described herein may be applied to the affected area ofthe skin of the patient. The frequency of application will depend onindividual patient circumstances. For example, the compositions may beapplied daily, twice daily, or even more frequently.

Methods and pharmaceutical carriers for preparation of pharmaceuticalcompositions, including compositions for topical administration are wellknown in the art, as set out in textbooks such as Remington'sPharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton,Pa., USA (updated in Gennaro, A. R., Remington: The Science and Practiceof Pharmacy, 20^(h) edition, Lippincott, Williams & Wilkins) which isincorporated by reference in its entirety.

DETAILED DESCRIPTION

In one aspect, the pharmaceutical compositions described herein can beused for the treatment of peripheral neuropathy. These compositions caninclude a therapeutically effective amount of ketamine, gabapentin andclonidine in a pharmaceutically acceptable diluent or carrier suitablefor transdermal or topical use. Preferably, the compositions comprise atleast ketamine, gabapentin and clonidine, in amounts sufficient topotentiate an antineuropathic response when the compositions areadministered transdermally in a physiologically acceptable transdermalvehicle.

As used herein “potentiated” or “synergistic” refers to anantineuropathic response or a pain-reducing response elicited throughthe synergistic effect of the compositions described herein, in whichthe combined effect of multiple agents is greater (in duration,intensity, comprehensively, or otherwise) than the sum of the effectproduced by each agent alone. The vehicle can allow the activeingredients to efficiently penetrate tissues when applied topically andcan allow increased concentrations of particular components (i.e.,ketamine) and all added analgesic agents in the compositions describedherein.

As used herein, “transdermal” or “percutaneous” delivery relates todelivery of a drug by passage into and through the skin or mucosaltissue. Hence the terms “transdermal”, “topical” and “transmucosal” areused interchangeably unless specifically stated otherwise. Likewise theterms “skin,” “derma,” “epidermis,” “mucosa,” and the like shall also beused interchangeably unless specifically stated otherwise.

The compositions described herein may provide one or more of thefollowing beneficial effects to a patient when topically applied ineffective amounts: relief of pain, burning, tingling, electricalsensations and/or hyperalgesia. Also increased microcirculation, nitricoxide stabilization, and facilitated healing of skin ulcers and lesions.Additionally, protein kinase C inhibition, decreased oxidative stress,anti-inflammation, protection against radiation damage (particularlyultraviolet radiation), blockage of the formation of leukotrienes,stabilization of cell membranes, and/or promotion of the synthesis ofnerve growth factor.

Ketamine is an N-methyl-D-aspartate (NMDA) calcium channel antagonistthat can be admixed in the compositions described herein inconcentrations ranging from 10-50%, preferably 10 to 30%, and mostpreferably from 15% to 20% safely. Topical ketamine is effective fortreating painful neuropathy when other traditional medicines havefailed. See Crowley K L, Flores J A, Hughes C N et al. “Clinicalapplication of ketamine ointment in the treatment of sympatheticallymaintained pain”, International Journal of Pharmaceutical Compounding1998; 2:122-127.

Gabapentin is a glutamate antagonist at the NMDA and AMPA (sodiumchannel) receptor sites. This agent can be admixed in strengths rangingfrom 1 to 30 percent, but preferably in strengths less than 10%. Themost preferred strength is 6%, but it can be reduced to 3% in case ofpronounced ataxia. Because gabapentin is almost entirely eliminated bythe renal route as unchanged drug, caution should be exercised with oraldosing (especially in renal-compromised patients.) More dosingflexibility is allowed transdermally because of its relatively lowsystemic concentration. Subsequent to the development of thecompositions described herein, it was discovered that gabapentin alsoprevents ketamine neurotoxicity. See Bakonja M, Baydoun A, Edwards K R,et al. “Gabapentin for the symptomatic treatment of painful neuropathyin patients with diabetes mellitus—a randomized controlled trial.” JAMA1998; 280: 1831-1836. Also see Rowbatham M, Hardin N, Stacey B, et al.“Gabapentin for the treatment of postherpetic neuralgia—a randomizedcontrolled trial.” JAMA 1998; 280: 1837-1842. Subsequent to thediscovery of the compositions described herein, it was discovered thatgabapentin prevents neurotoxicity of certain compounds, see Farber, N B,et al. “Antiepileptic drugs and agents that inhibit voltage-gated sodiumchannels prevent NMDA antagonist neurotoxicity.” Mol Psychiatry 2002;7(7): 726-733.

Clonidine is an α-2 agonist that blocks norepinephrine release fromsympathetic nerve endings. It also potentiates the action of ketamine.It can be admixed in strengths ranging from 0.001% to 2%, with thepreferred strength ranging from 0.1 to 1%, the most preferred strengthbeing 0.2%. See Hoffman BB, Lefkowitz RJ. “Catecholamines,sympathomimetic drugs and adrenergic receptor antagonists” in Goodman &Gilman's The Pharmacological Basis of Therapeutics, ed. 10; New York,McGraw-Hill.

Without being bound to any particular theory of mechanism, thecompositions described herein provide an antineuropathic response with acombination of drugs which synergistically or comprehensively affectmultiple pathways associated with neuropathies, i.e., a synergistic“shotgun” effect. Again, without being bound to any particular theory ofmechanism, it is proposed that the compositions described herein involvea double synergism. First, gabapentin is a glutamate antagonist; henceit's an effective analgesic. It also prevents the neurotoxicity ofketamine—a potent analgesic—thus allowing increased ketamineconcentrations that will effect greater analgesia. Second, clonidine isan α-2 agonist acting against pain stimuli. It also potentiates theaction of ketamine.

In an alternative embodiment of the compositions described herein,clonidine can be substituted with an alternative analgesic. Suchanalgesics contemplated by the compositions described herein potentiatethe action of ketamine. The analgesics can be any known in the art,including, but not limited to NMDA ligands, AMPA ligands, non-NMDA orAMPA ligands, TNF-1α ligand, GABA ligand, α-2 ligands, and the like.Such analgesics can include clonidine, capsaicin, lidocaine,bupivacaine, mepivacaine, ropivacaine, tetracaine, etidocaine,chloroprocaine, prilocaine, procaine, benzocaine, dibucaine, dycloninehydrochloride, pramoxine hydrochloride, benzocaine, and proparacaine.Those of skill in the art will readily recognize additional ingredientsthat can be admixed in the compositions described herein.

The topical pharmaceutical compositions described herein can furthercomprise alternative NMDA receptor antagonists, as an alternative toketamine or as a supplemental analgesic. These antagonists can becompetitive or non-competitive drugs. The NMDA receptor antagonist canbe any known in the art, including, but not limited to dextromethorphan,dextrorphan, pyroloquinoline quinone,cis-4-(phosphonomethyl)-2-piperdine carboxylic acid, MK801, memantine,and their mixtures and pharmaceutically acceptable salts thereof.

In addition, the compositions described herein can further compriseadditional ingredients which can increase the analgesic effectiveness ofthe combination of ketamine, gabapentin and clonidine. Such ingredientseither facilitate the effect of this combination by increasingabsorption and/or penetration, provide for a more comprehensive painmanagement regimen, or the like. Those of skill in the art will readilyrecognize additional ingredients that can be admixed in the compositionsdescribed herein. Preferably, the compositions described herein cancomprise one or more of the following ingredients:

AMITRIPTYLINE 1% to 10%, Preferably 2% to 5% in Composition.

This tricyclic agent is a norepinephrine reuptake inhibitor. It can beused in strengths of 2% to 5%. See Goodkind K, Vrancken M A E, FeasterD. “On the putative efficacy of antidepressants in chronic, benign painsyndrome—an update.” Pain Forum 1995; 4:237-247.

BACLOFEN 1% to 10%, Preferably 2% to 5% in Composition.

This drug is a GABA_(β)-agonist possessing presynaptic depressant actionat NMDA and non-NMDA receptors. It can be used in strengths of 2% to 5%.See Evans R H, “The importance of NMDA receptors in the processing ofspinal afferent input” in Collingridge G L, Watkins J C (Eds), The NMDAReceptor (2nd ed), New York, Oxford University Press, 1994; pp 266-276.

CAPSAICIN 0.001% to 0.1%, Preferably 0.025% in Composition.

This substance is a Substance P blocking agent currently used in astrength of 0.025%. It is a useful adjunct, but sometimes causesexcessive skin irritation. The 0.025% strength is to prevent extremedermal irritation). See Tandan R, Lewis G A, et al. “Topical capsaicinin painful diabetic neuropathy—a controlled study with long-term followup” in Diabetes Care 1992; 15:8-14.

LOPERAMIDE 1% to 20%, Preferably 5% to 10% in Composition.

This anti-diarrheal agent is a Mu-agonist (similar to morphine, butwithout morphine's systemic side effects.) It can be added to thecompositions described herein in strengths of 5% to 10%. SeeNozaki-Taguchi N, Yaksh T L. “Characterization of the antihyperalgesicaction of a novel peripheral mu-opioid receptor agonist—loperamide” inAnesthesiology 1999; 90:225-234.

NIFEDIPINE 1% to 25%, Preferably 2% to 15% in Composition.

This drug is a non-NMDA calcium channel antagonist. It offers anadditional protective effect with ketamine to block glutamate insult.This calcium channel blocker is especially useful for treating diabeticperipheral neuropathy. The agent can be added to the compositionsdescribed herein in strengths of 2% to 15% depending on the size of thetreatment area. Due to circulatory and hypotension considerations,higher strengths may be used for areas below the waist (e.g., the feet)and lower strengths for areas above the waist. See Robertson S, et al.“The effects of the calcium antagonist nifedipine on peripheral nervefunction in streptozotocin-diabetic rats” in Diabetologia 1992;35:1113-1117.

PENTOXIFYLLINE 1% to 25%, Preferably 5% to 10% in composition.

This vasodilator, a TNF-1α antagonist., is useful for low back pain. Itcan be added to the compositions described herein in strengths of 5% to10%. See Yabuki S, et al. “Prevention of compartment syndrome in dorsalroot ganglia caused by exposure to nucleus pulposus” in Spine 2001;26:870-875.

The compositions described herein can further comprise componentsusually admixed in such preparations (besides ketamine, gabapentin andat least one additional analgesic, preferably clonidine). For example,the compositions may also include additional ingredients such as othercarriers, moisturizers, oils, fats, waxes, surfactants, thickeningagents, antioxidants, viscosity stabilizers, chelating agents, buffers,preservatives, perfumes, dyestuffs, lower alkanols, humectants,emollients, dispersants, sunscreens such as radiation blocking compoundsor particularly UV-blockers, antibacterials, antifungals, disinfectants,vitamins, antibiotics, or other anti-acne agents, as well as othersuitable materials that do not have a significant adverse effect on theactivity of the topical composition. Additional ingredients forinclusion in the carrier are sodium acid phosphate moisturizer, witchhazel extract carrier, glycerin humectant, apricot kernel oil emollient,corn oil dispersant, and the like which are further detailed below.Those of skill in the art will readily recognize additional ingredients,which can be admixed in the compositions described herein.

The compositions described herein can be made by cold compounding. Thisis significant since one or more of the compounds admixed in the topicalcompositions described herein are sensitive to heat or other types ofenergy. Thus the activity of the composition may be detrimentallyaffected as a result of the formulation of the compositions in othermanners. Hence, the ingredients of this topical composition are merelymixed together, without heating and using a sufficient amount of thecarrier to provide a substantially homogeneous cream or ointment. It isgenerally preferred to dissolve, disperse or suspend one or more of theingredients prior to cold compounding in order to ensure substantiallyhomogeneous distribution of the active ingredients in the composition.

In addition to the foregoing components, the compositions describedherein can optionally contain other ingredients. For example,triethanolamine can be added as a crosslinking agent. A preservative,such as betahydoxytoluene can also be added. Other irritation reducingagents can be added too. In this regard, irritation reducing agents caninclude, but are not limited to, glycerol. In some instances, semi-solidtestosterone formulations have been prepared with propylene glycoland/or butylene glycol as the glycol component, ethyl alcohol and/orisopropyl alcohol as the alcohol component. Preservatives, across-linking agent, and additional irritation reducing agents can beincluded in formulations prepared in accordance with the methodsdescribed.

In other aspects, the methods described herein can include treatingperipheral neuropathy, comprising the step of topical administration ofa pharmaceutical composition of ketamine, gabapentin and clonidine (oralternative analgesic as described herein) to the affected area of asubject in need of such treatment. In preferred embodiments the methodsdescribed herein can provide a treatment of applying the compositionsdescribed herein to an affected area of a subject with diabeticpolyneuropathy.

Other peripheral neuropathies include the following: HIV associatedneuropathy; B₁₂-deficiency associated neuropathy; cranial nerve palsies;drug-induced neuropathy; industrial neuropathy; lymphomatous neuropathy;myelomatous neuropathy; multi-focal motor neuropathy; chronic idiopathicsensory neuropathy; carcinomatous neuropathy; acute pan autonomicneuropathy; alcoholic neuropathy; compressive neuropathy;vasculitic/ischaemic neuropathy; mono- and poly- neuropathies.

Thus, the methods and compositions described herein can be effective forneuropathies associated with systemic diseases such as: uremia;childhood cholestatic liver disease; chronic respiratory insufficiency;alcoholic polyneuropathy; multiple organ failure; sepsis;hypo-albuminemia; eosinophilia-myalgia syndrome; hepatitis; porphyria;hypo-glycemia; vitamin deficiency; chronic liver disease; primarybiliary cirrhosis; hyperlipidemia; leprosy; Lyme disease; herpes zoster;Guillain-Barre syndrome; chronic inflammatory demyelinatingpolyradiculoneuropathy; sensory perineuritis; acquired immunodeficiencysyndrome (AIDS)—associated neuropathy; Sjogren's syndrome; primaryvasculitis (such as polyarteritis nodosa); allergic granulomatousangiitis; hypersensitivity angiitis; Wegener's granulomatosis;rheumatoid arthritis; systemic lupus erythematosis; mixed connectivetissue disease; scleroderma; sarcoidosis; vasculitis; systemicvasculitides; acute tunnel syndrome; pandysautonomia; primary,secondary, localized or familial systemic amyloidosis; hypothyroidism;chronic obstructive pulmonary disease; acromegaly; malabsorption (sprue,celiac disease); carcinomas (sensory, sensorimotor, late anddemyelinating); lymphoma (including Hodgkin's), polycythemia vera;multiple myeloma (lytic type, osteosclerotic, or solitary plasmacytoma);benign monoclonal gammopathy; macroglobulinemia; cryoglobulinemia;tropical myeloneuropathies; herpes simplex infection; cytomegalovirusinfection; and diabetes.

Genetically acquired neuropathies suitable for treatment by the methodsand compositions described herein include, without limitation: peronealmuscular atrophy (Charcot-Marie-Tooth Disease) hereditary amyloidneuropathies, hereditary sensory neuropathy (type I and type II),porphyric neuropathy, hereditary liability to pressure palsy, Fabry'sDisease, adrenomyeloneuropathy, Riley-Day Syndrome, Dejerine-Sottasneuropathy (hereditary motor-sensory neuropathy-III), Refsum's disease,ataxia-telangiectasia, hereditary tyrosinemia, anaphalipoproteinemia,abetalipoproteinemia, giant axonal neuropathy, metachromaticleukodystrophy, globoid cell leukodystrophy, and Friedrich's ataxia.

In alternative embodiments compositions described herein are directed totreatment of neuropathic pain, especially pain caused by nerve injury orsympathetically mediated pain. Sympathetically mediated pain (SMP) is atype of pain in which over activity of the sympathetic nervous systemplays a crucial role. It includes the syndromes of reflex sympatheticdystrophy, causalgia, neuropathic pain secondary to nerve injury, andpain from neuromas. It encompasses all neurogenic pain that is notcentral and is related to a nerve injury regardless of the cause.Neuropathic pain syndromes include, without limitation (other than theneuropathies described herein), allodynia, various neuralgias such aspost herpetic neuralgia and trigeminal neuralgia, phantom limb pain,hyperpathia, hyperesthesia, hyperalgesia, dyesthesia, paresthesia,anesthesia delorosa, deafferentation pain, and complex regional painsyndromes, such as reflex sympathetic dystrophy and causalgia. Specificexamples include low back pain, sciatica, Guillain-Barre Syndrome,post-surgical traumatic neuropathy, and diabetic peripheralpolyneuropathy.

Methods described herein can also involve the topical application of acomposition described herein to areas of the skin in the vicinity oftissue that suffers from the neuropathic pain. In particular, thecompositions and methods described herein are useful on the patients'extremities such as the peripheral appendages (e.g., fingers, toes,hands and feet) and general areas of pain (e.g., back, shoulder, neck)where the neuropathic pain, particularly peripheral neuropathy, is oftenthe most pervasive. The methods and compositions described herein canalso applied to the specific ganglia that mediate pain to the spinalcolumn and to the spine itself. Specific dermatomes are involved for thecorrect application of the compositions described herein for neuropathicanalgesia.

For example, a suitable amount of a composition described herein can beapplied one to six times daily as needed to relieve pain and othersymptoms of diabetic polyneuropathy. Preferably, the composition isapplied two to four times daily, as needed for pain. A sufficient amountis applied to cover the area afflicted by the diabetic polyneuropathywith a thin layer of the composition and the composition is rubbed intothe skin until little or no residue remains on the skin. Treatmentbegins initially to treat acute symptoms but may be continuedindefinitely to relieve pain, prevent symptoms of diabeticpolyneuropathy from returning and possibly restore some nerve and/orskin function. The application frequency and volume of the compositionmay decrease over time, but not necessarily.

The methods described herein may also provide one or more of thebeneficial effects described above for the compositions describedherein. In addition, methods described herein can provide someadditional beneficial effects due to one or more of the ingredientscontained in the pharmaceutically acceptable carrier such as describedabove, e.g., the return of sensory perception at the application site.

The methods described herein also encompass topical administration ofcompositions in a physiologically acceptable transdermal vehicle and inan amount and duration sufficient to provide an antineuropathicresponse. Administration to the subject is performed in accordance withthat mode which is most amenable to the topically acceptable formchosen. For example, gels, lotions, creams, and ointments are preferablyadministered by spreading. Because hydrated skin is more permeable thandry skin, the dosage form can be modified or an occlusive dressing canbe applied to facilitate absorption. Also contemplated by thecompositions and methods described herein are slow-release orsustained-release forms, whereby a relatively consistent level of thecomposition, particularly ketamine, gabapentin and at least oneadditional analgesic are provided over an extended period.

A subject can be treated in accordance with the compositions describedherein by administering the composition suspended in or admixed with aphysiologically suitable transdermal vehicle and manually applied orsprayed (either with a manually-actuated pump or with the aid of asuitable pharmaceutically-acceptable propellant) onto the surface areain need of treatment. Preferably, the composition is applied by topicalmassage. Suitable formulations for topical application of drugs are wellknown to those of ordinary skill in the art and can be routinelyselected.

The amount of composition to be applied varies on the choice of vehicleas well. For example, when the composition is administered by sprayingan alcoholic liquid solution of the drug, the total volume in a singledose can be very low. Conversely, when the compositions described hereinare administered in a transdermal cream, the total volume can be higher.The vehicle selected and its manner of application is preferably chosenin consideration of the needs of the patient and the preferences of theadministering medical practitioner.

The general mode of action of the compositions described herein isthrough “transdermal administration.” This mode of action is restrictedto the region below the surface of the dermis where the drug applicationhas occurred. In using the transdermal route of administration, theamount of composition absorbed systemically is minimal. This isespecially true when the application site(s) is/are below the beltline.Transdermal administration of the compositions described herein isdirected to cutaneous surfaces. The composition can be appliedtransdermally on a subject in an amount and duration sufficient toprevent or relieve pain associated with any cause, including, but notlimited to, neuropathic inflammation, and acute and chronic peripheralneuropathy.

Transdermal application of the compositions described herein is usefulfor relieving pain, inflammation and irritation associated with skindiseases and disorders. Painful lesions develop, for example, from viralinfections, i.e., herpes zoster, skin cancers and genetic disorders.Acute post-operative or surgical pain can be reduced or even eliminatedas can pain associated with chronic disorders, such as diabeticperipheral polyneuropathy.

The formulations in which the compositions described herein areincorporated can assume any of a variety of dosage forms, includingsolutions, suspensions, ointments, and solid inserts. Examples arecreams, lotions, gels, ointments, suppositories, sprays, foams,liniments, aerosols, buccal and sublingual tablets, various passive andactive transdermal devices for absorption through the skin and mucousmembranes, and the like.

Typical pharmaceutically acceptable carriers are, for example, water,mixtures of water and water-miscible solvents such as lower alkanols orvegetable oils, and water-soluble ophthalmologically acceptablenon-toxic polymers, for example, cellulose derivatives such asmethylcellulose. A typical cream or ointment-type carrier for topicalapplication that can be used according to the methods and compositionsdescribed herein include a mixture of water, glycerin, propylene glycol,and methylparaben. Topical carriers may also include other conventionalemulsifiers and emollients including alginates, glyceryl stearate,PEG-100 stearate, cetyl alcohol, propylparaben, butylparaben, sorbitols,polyethoxylated anhydrosorbitol monostearate (TWEEN), white petrolatum(VASELINE), triethanolamine, Emu oil, aloe vera extract, lanolin, cocoabutter, and the like. Suitable topical carriers are well known to theskilled artisan. Standard texts, such as Gennaro, A. R., Remington: TheScience and Practice of Pharmacy, 20^(h) edition, Lippincott, Williams &Wilkins; Hardman, J. G., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 10^(th) edition, McGraw-Hill Professional; Shah & Maibach,Topical Drug Bioavailability, Bioequivalence, and Penetration, 1stedition, Plenum Pub Corp.; Hillery et al., Drug Delivery and Targeting:For Pharmacists and Pharmaceutical Scientists, Harwood Academic Pub.;Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thedition, Lippincott Williams & Wilkins (each incorporated herein byreference), can be consulted to prepare suitable compositions fortopical administration, without undue experimentation. Suitable dosagescan also be determined based upon the text and documents cited herein.Characteristics which determine preferred carriers include ease ofapplication, hypoallergenicity, the ability to contain a minimum of 30%of its weight in active drugs, aesthetically pleasant, and the abilityto permeate/penetrate the skin.

Preferably, Lipoderm® (Professional Compounding Centers of America,Houston, Tex.) is admixed in the compositions described herein.Alternative ointment bases are known to persons skilled in the art.Sufficient Lipoderm® base is admixed to act as a carrier for the activeingredients of the composition. Typically the Lipoderm® base will makeup more than about 70% of the total composition and more preferablyabout 74% of the composition is the Lipoderm® base. The Lipoderm® basefunctions as a carrier and enhances penetration into the skin. It isalso hypoallergenic and is aesthetically pleasing.

A typical transdermal gel base, provided herein for exemplary purposesonly, can contain lecithin, isopropyl palmitate, poloxamer 407, andwater. Topical carriers with different viscosities and hand-feel areknown to the art. The above active ingredients can be dispersed withinthe pharmaceutically acceptable carrier in therapeutically effectiveamounts to treat neuropathies, and the other maladies described above.Preferably, the topical pharmaceuticals described herein contain (pergram total weight) from about 15 grams per 100 gram weight of ketamine,from about 6 grams per 100 grams weight of gabapentin, and from about0.2 grams per 100 grams weight of clonidine. Other analgesic agents canbe added accordingly, e.g., capsaicin.

Transdermal dosage unit forms can be prepared utilizing a variety oftechniques that have been described in the art. For example, in U.S.Pat. Nos. 4,861,800; 4,868,218; 5,128,145; 5,190,763; and 5,242,950; andin the foreign patent documents EP-A 404807; EP-A 509761; and EP-A593807. (each of which is incorporated by reference in its entirety). Amonolithic patch structure can be utilized in which selegiline isdirectly incorporated into the adhesive and this mixture is cast on to abacking sheet. Alternatively, selegiline as an acid addition salt can beincorporated into a multi layer patch which effects a conversion of thesalt to selegiline-free base, as described for example in EP-A 593807.One can also employ a device using a lyotropic liquid crystallinecomposition in which, for example, 5-15% of selegiline is combined witha mixture of liquid and sold polyethylene glycols, a polymer, and anon-ionic surfactant, optionally with the addition of propylene glycoland an emulsifying agent. For further details on the preparation of suchtransdermal formulations, reference can be made to EP-A 509761.

“Drug delivery system,” “drug/enhancer composition,” or any similarterminology relates to a formulated composition containing the drug tobe transdermally delivered in combination with a penetration enhancer.Other pharmaceutically acceptable materials or additives can also becontained in the drug/enhancer composition, such as a diluent,skin-irritation reducing agent, carrier or vehicle, excipient,plasticizer, emollient, or other additive and mixtures thereof providedthat such additives do not materially affect the basic and novelcharacteristics of the matrix patch.

The terms “matrix,” “matrix system,” or “matrix patch” relate to anactive permeant or drug dissolved or suspended in a biocompatiblepolymeric phase, preferably a pressure sensitive adhesive, that can alsocontain other ingredients or in which the enhancer is also dissolved orsuspended. This definition is meant to include embodiments wherein suchpolymeric phase is laminated to a pressure sensitive adhesive or usedwith an overlay adhesive. A matrix system usually and preferablycomprises an adhesive layer having an impermeable film backing laminatedonto the distal surface thereof and, before transdermal application, arelease liner on the proximal surface of the adhesive. The film backingprotects the polymeric phase of the matrix patch and prevents release ofthe drug and/or enhancer to the environment. The release liner functionssimilarly to the impermeable backing, but is removed from the matrixpatch prior to application of the patch to an application situs. Matrixpatches are known in the art of transdermal drug delivery to routinelycontain such backing and release liner components, and matrix patchesaccording to the compositions described herein should be considered tocomprise such backing and release liner or their functional equivalents.U.S. Pat. No. 5,122,383 (incorporated herein by reference) describessuch backing and release liner. A matrix system therefore relates to aunit dosage form of a drug composition in a polymeric carrier, alsocontaining the enhancer and other components that are formulated formaintaining the drug composition in the polymeric layer in a drugtransferring relationship with the derma, i.e. the skin or mucosa. Amatrix patch is distinguished from a “liquid reservoir patch,” whereinan active permeant or drug is dissolved in a gelled liquid contained inan occlusive device having an impermeable back surface and an oppositesurface configured appropriately with a permeable membrane and adhesivefor transdermal application, e.g., U.S. Pat. No. 4,983,395, incorporatedherein by reference in its entirety.

A typical transdermal formulation comprises a conventional aqueous ornon-aqueous vehicle, for example, a cream, ointment lotion or paste orin the form of a medicated plaster, patch or membrane.

The pharmaceutical preparation may also contain non-toxic auxiliarysubstances such as emulsifying, preserving, wetting, and bodying agents,as for example, polyethylene glycols; antibacterial components such asquaternary ammonium compounds; buffering ingredients such as alkalimetal chloride; antioxidants such as sodium metabisulfite; and otherconventional ingredients such as sorbitan monolaurate.

The term “effective amount” of a drug or permeant relates to a nontoxicbut sufficient amount of a compound to provide the desired local orsystemic effect without adverse side effects. An “effective amount” ofpermeation enhancer as used herein relates to an amount selected so asto provide the desired increase in membrane permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug.

As used herein, “application situs” relates to a site suitable fortopical application with or without the means of a device, patch, ordressing, e.g. the spinal column, behind the ear, on the arm, back,chest, abdomen, leg, top of foot, etc.

The penetration enhancing compositions of the compositions describedherein may constitute a small amount of the formulation or a largeamount depending on which transdermal vehicle is used, whichsystemically and/or topically active agent is used, and the type ofbiological effect sought. The amount will be readily apparent to thoseskilled in the art, since the total amount of penetration enhancers willbe approximately the same as those of the prior art. For example, whenthe potency of the penetration enhancement composition is greatlyincreased, lower quantities can be used.

Subjects to whom the formulations can be administered are primarilymammals, including humans, pets, and livestock and other farm animalsand sport animals. The compositions and methods described herein arepreferably used on humans. The term “topical administration” or “topicalapplication” refers to directly layering or spreading upon epidermaltissue, especially outer skin or membrane, including the skin ormembrane of the oral or vaginal cavities.

The site of application is dependent on many factors including, but notlimited to, the amount of drug to be delivered, the extent ofenhancement required, the side effects manifested and the time ofapplication. Thus, another important facet of the methods describedherein is the use of these compositions with drugs other than forexample, testosterone, or to apply such formulations, or topicalproducts in general, specifically to the soles of the feet, the palms ofthe hands or other immune-privileged sites of the body. Also, the drugs,compositions or products may be administered later in the day or atnight when the permeability at the site of application is higher.

The amount of composition necessary to produce a therapeutic effect atan affected area is based on various factors, including the strength ofthe active ingredients, the ingredients admixed, the pain type andintensity, or related to, the location and size of the area and therelative condition that is to be treated. For example, the amount ofcomposition needed to treat severe pain is likely to be greater than theamount of composition needed to treat mild to moderate forms of theaffliction. In addition, an acute condition will likely require lessmedication for less time than a chronic condition. Individualsensitivities will also influence the dosage amounts administered to aparticular subject. A determination of the appropriate dose is withinthe skill of one in the art given the parameters herein. In terms of thecompositions described herein, the preferred dosage range is preferablydetermined by considering the amount of ketamine, gabapentin and atleast one additional analgesic delivered, in percentage, and the surfacearea to be treated. The concentration of the active ingredients, in thepharmaceutical composition can be from about 0.001% to about 50%ketamine, about 0.001% to about 50% gabapentin, 0.001% to about 2%clonidine, and about 0.001% to about 0.1% capsaicin. In accordance withthe compositions and methods described herein, the foregoing doses canbe readily optimized following the teachings herein, based on knownpharmacological protocol, by those of ordinary skill in the art, with nomore than routine optimization. Of course, the preferred lower limit fordrug delivery is that necessary to bring about an anti-neuropathiceffect. The preferred upper limit is less than that amount whichproduces untoward side effects.

Although not crucial, the dilution and/or formulation of the activeingredients of the compositions described herein, in a physiologicallyacceptable transdermal vehicle, can be important and useful in providingthe final dosage concentration. The compositions can be supplied insolid, semi-solid or liquid forms, including tablets, capsules, powders,liquids, and suspensions. The compositions described herein cantherefore encompass concentrated forms for subsequent dilution beforeuse or sale. Thecompositions can comprise any physiologically acceptabletopical excipients including, but not limited to, gels, lotions, creams,ointments, and liquids.

EXAMPLES

The active ingredients of the compositions described herein are composedof three chemicals within a transdermal base. The chemicals are (1)ketamine, an N-methyl-D-aspartate (NMDA) calcium channel antagonist. Itcan be used safely in preferable concentrations of 15% or 20% whencombined with gabapentin. (2) Gabapentin, a glutamate antagonist at theNMDA and AMPA (sodium channel) receptor sites. Its concentration istypically 6%, but can be reduced to 3% or less for gabapentin-sensitivepatients. Gabapentin also prevents ketamine neurotoxicity. (3)Clonidine, an α-2 agonist that blocks nor-epinephrine release fromsympathetic nerve endings. It also potentiates the action of ketamine.Its concentration in the formula is 0.2%, but can be further reduced oreliminated for clonidine-allergic patients. Eliminating clonidine,however, will result in a less-than-optimal analgesic compound. Thetransdermal vehicle Lipoderm® is used. It has the exceptional ability tocontain up to 50% of its weight in active drugs. It is also cosmeticallyelegant and has a hypoallergenic compatibility with human dermis. Thecombination of the 3 agents within the Lipoderm® base actsynergistically to relieve neuropathic pain.

Side effects are possible with the compositions described herein,especially drowsiness and/or dizziness. For example, Gabapentin is knownto cause ataxia when taken orally as an oral capsule or tablet.Clonidine is a potent hypotensive agent, and hence, at times canmarkedly reduce blood pressure. Transdermal application usually preventsthese potential side effects. Follow-up surveys have proven this.

One preferred method of preparation is as follows. Clonidine wastriturated to a fine powder. Clonidine, ketamine, and gabapentin powderswere filtered through a fine-mesh screen into the appropriate vessel(e.g., a glass mortar.) Powders were wetted with sufficient propyleneglycol. Some Lipoderm® was added to suspend the wet powders. Theremainder of Lipoderm® was added and triturated till mixed. Krisgel® 1%(of the total compound) was added to thicken. An ointment mill was usedto completely mix and smooth the cream. The resulting cream looked andfelt like custard.

Administration

The compositions described herein may be applied two ways via massage:(1) directly to the pain site or appropriate ganglion and (2) into theappropriate dermatome on the spine.

Plan 1 is normally used first, especially if the pain locus is below thebelt (due to reduced systemic circulation of the agents.) The patient isinstructed to find the most precise area of pain—if possible—by using ablunt, pointed object (i.e., fingertip, pen tip, etc.) By use of a“checkerboard pattern” search, many times the pain locus is discovered.For example, a foot pain locus may be found by pressing a fingertip onone side of the ankle for approximately 2 seconds then moving thefingertip an inch towards the other side of the ankle. This pressure isrepeated “checkerboard style”(across and downward) until the entirefoot—top and bottom—has been covered. The patient takes note of whatarea(s) hurt most and then treats the area(s) with ½ gram or 1 gram ofcream at each pain site. If a precise locus cannot be found, then a 1gram dose to the nerve bundle located ¾ inch below and ¾ inch behind theinside anklebone will suffice. This nerve bundle is responsible forinnervation of the foot via the L-4, L-5, S-1, and S-2 dermatomes. Otherganglia may be used similarly for pain loci at other anatomical sites.An anesthesiologist—or a medical professional with a thoroughunderstanding of human anatomy—should be consulted for the mostappropriate ganglion (or ganglia) to be used.

Plan 2 is used when there is insufficient analgesia provided by Plan 1.Plan 2 requires massage of the cream into the appropriate dermatome onthe spinal column. The patient is shown where the correct dermatomeapplication site (on the spine) is for the painful area described by thepatient. For example, a foot pain locus requires cream application tothe L-4, L-5, S-1, and S-2 vertebrae on the spine.

How much cream to apply depends on (1) the pain site and (2) painseverity. The patient is instructed to use Plan 1 first. During thecounseling session, the patient learns to (1) find the pain using the“checkerboard technique” described above and (2) prepare the skin forapplication by warming the site with a very warm, slightly moist cloth.A minimum dose—usually between ½ to 1 gram—is suggested as a startingdose. A (1-gram+½ gram) dosing spoon is given to the patient foraccurate measure. The patient is instructed to use this starting dose 3times daily for 3 days unless side effects appear. If that happens, thepatient is counseled to immediately cease the applications and callhis/her doctor. After the 3 day period—and if no sign of analgesia norside effects—the dose may be increased by ½ gram increments daily. Forexample, if a 1-gram dose to the site did not relieve the pain duringthe first 3 days, then the dose would be increased by ½ gram perapplication on day 4. If the pain was still not managed, the dose wouldbe increased by another ½ gram dose on day 5. The dose total at thatpoint would be 2 grams per application. This sequence would be repeateduntil (1) the pain is managed or (2) side effects begin. Note: Sideeffects at any time are the limiting factor for dosing.

If Plan 1 does not provide sufficient analgesia within 7 days of thefirst application, then the patient is instructed to initiate Plan 2.Application to this area is explained above. Because the area is abovethe belt line, the patient is told that there is an increased risk ofside effects. A 1-gram dose at the correct dermatome is started with theproviso that the dose may be adjusted down or up after a 3 day dosingperiod. This is similar to Plan 1.

Dosing frequency is dependent on the cream's duration of action.Duration of action varies from patient to patient. Normally, the creamis applied 3 times daily, but more frequent—or lessfrequent—applications are possible. Again, the limiting factor is sideeffects. Hence, if no side effects, then multiple daily applications areOK. The cream is a pain management “tool”. As such, the cream may beused as often as necessary (subject to side effects.)

Objectives and Advantages

Pain management is one objective of the compositions and methodsdescribed herein. The methods and compositions described herein canameliorate neuropathic pain in patients. The compositions and methodsdescribed herein have the following advantages: (1) Surveys have shownthat >75% of patients using the compositions described herein havemanaged their neuropathic pain with at least one embodiment describedherein; (2) the compositions described herein are effective against awide variety of sympathetically mediated pain (SMP) sources—includingvarious neuropathies, low back pain, sciatica, and post-spinal surgerypain; (3) the doses needed to control neuropathic pain are relativelysmall (see survey, Table 1); (4) dose volumes are also small—a distinctapplication advantage; (5) patients affected by side effects total lessthan 22% (includes those who “failed” the cream); (6) the compositionsdescribed herein are cosmetically elegant; (7) the compositionsdescribed herein are easy to apply because they are readily absorbed bythe prepared skin.

TABLE 1 Initial Pain Application I. Number Level (10- Amount FrequencyPain Level: Duration of Patients Compound Components point scale)Applied (Times/day) One Week of Action 8 Ketamine 10% + Gabapentin 6% +7.3 1.4 grams 1.8/day 3.0 5.1 hours Clonidine 0.2% in aPluronic-Lecithin- Organogel Transdermal Vehicle 66 Ketamine 15% +Gabapentin 6% + 7.9 1.5 grams 1.9/day 3.9 7.9 hours Clonidine 0.2% inPLO or Lipoderm ® Transdermal Vehicle 8 Ketamine 15% + Gabapentin 6% +8.0 1.5 grams 2.1/day 4.0 5.5 hours Clonidine 0.2% + Capsaicin 0.025% inPLO or Lipoderm ® 17 Ketamine 20% + Gabapentin 6% + 8.3 1.9 grams2.2/day 4.0 4.4 hours Clonidine 0.2% in PLO or Lipoderm ® TransdermalVehicle

Table 1 above describes the most commonly used varieties of thecompositions described herein. A subjective 10-point pain scale was usedby the patients at baseline and at 7 days to describe their pain. A “1”essentially meant no pain. A “10” described very severe pain—the kindthat leaves one in agony. The amount applied was judged by the number of1 gram—½ gram dispensing spoons used per application. There wastremendous Application Frequency variability. Application times rangedfrom every other day to 5 times daily.

Onset of analgesia for all four composition varieties share the sametime period. These times varied from a half hour to over 72 hours. Forreasons not known, the onset times differed from patient to patient.

Compound #1 achieved a pain reduction of 4.3 points =59% pain reduction.In the survey, 14 people used the 10% strength PLO-based(pluronic-lecithin organogel) transdermal gel but 6 reported treatmentfailure. This represents a success rate of 57%. But the 14 patients whoused this gel represent a statistically small sample. It was noticedearly on that about 50% of patients were experiencing sufficientanalgesia. Subsequently, the Ketamine amounts were increased and thencapsaicin was added to the basic formula.

Compound #2 achieved a pain reduction of 4 points=a 51% pain reduction.Note that the baseline pain level is 0.6 points higher than for the 10%gel. Also, more people (#87) have used the 15% strength of thecompositions described herein than any other formulation. There were 21reported failures. The 66 patients who successfully used this 15%combination (a success rate of 76%) represent a statisticallysignificant sample.

Compound #3 also achieved a pain reduction of 4 points, and this=a 50%pain reduction. The baseline pain level was 0.1 point higher than the15% compound, but the increased analgesia expected due to the additionof Capsaicin did not materialize statistically. The small sample size—9patients with 1 failure—is probably responsible. But since there was asuccess rate of 89%, this combination is worth keeping. This embodimenthas now been replaced by ketamine 20% plus Capsaicin .025%, which wasshown to be much more effective. It is used when there is some—butinsufficient—analgesia achieved with differing embodiments of thecompositions described herein. See description of Compound #4 (below)for further discussion.

Compound #4 scored best, based on the illustrated statistics. With apain reduction of 4.3 points from a baseline pain level of 8.3, painreduction averaged 52% for the 17 patients who responded to the survey.The success rate of 85% is noteworthy (17 favorable responses and 3failures). As noted in paragraph 3, the 20% Ketamine combination withCapsaicin added should prove to be the best.

All publications and patent documents cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing methods and compositions have been described insome detail by way of illustration and example for purposes of clarityof understanding, it will be readily apparent to those of ordinary skillin the art in light of the teachings of these methods and compositionsthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1. A topical formulation for treating a subject suffering fromperipheral neuropathy, comprising: ketamine in an amount of greater than10% by weight; a glutamate antagonist; and a third compound whichpotentiates the activity of the ketamine.
 2. The topical formulation ofclaim 1, wherein glutamate antagonist comprises gabapentin.
 3. Thetopical formulation of claim 1, wherein the ketamine is in an amount ofgreater than 15% by weight.
 4. The topical formulation of claim 1,wherein the ketamine is in an amount of greater than 20% by weight. 5.The topical formulation of claim 1, wherein the third compound comprisesclonidine.
 6. The topical formulation of claim 1, wherein thecomposition comprises gabapentin in an amount of less than 10% byweight.
 7. The topical formulation of claim 1, wherein the thirdcompound is selected from an NMDA ligands, AMPA ligands, non-NMDA orAMPA ligands, TNF-1α ligand, GABA ligand and α-2 ligands.
 8. The topicalformulation of claim 1, wherein the third compound is selected from anSubstance P blocking agent, a Mu-agonist, a non-NMDA calcium channelantagonist, or a TNF-1α antagonist.
 9. The topical formulation of claim1, wherein said formulation is in a form selected from the groupconsisting of: cream, lotion, gel, oil, ointment, suppository, spray,foam, liniment, aerosol, buccal and sublingual tablet or a transdermaldevice for absorption through the skin or mucous membranes.
 10. Thetopical formulation of claim 9, wherein the formulation has an ointmentbase that makes up more than about 70% of the total formulation.
 11. Atopical composition for treating a subject suffering from peripheralneuropathy, said composition comprising an effective amount of ketamine,a glutamate antagonist and a third analgesic which potentiates theactivity of ketamine, formulated in a pharmaceutically acceptabletopical carrier.
 12. The topical composition of claim 11, wherein theglutamate antagonist comprises gabapentin.
 13. The topical compositionof claim 11, wherein the composition comprises ketamine in an amount ofgreater than 10% by weight.
 14. The topical composition of claim 11,wherein the ketamine is in an amount of greater than 15% by weight. 15.The topical composition of claim 11, wherein the third compoundcomprises clonidine.
 16. The topical composition of claim 11, whereinthe composition comprises gabapentin in an amount of less than 10% byweight.
 17. The topical composition of claim 11, wherein the thirdcompound is selected from an NMDA ligands, AMPA ligands, non-NMDA orAMPA ligands, TNF-1α ligand, GABA ligand and α-2 ligands.
 18. Thetopical composition of claim 11, wherein the third compound is selectedfrom an Substance P blocking agent, a Mu-agonist, a non-NMDA calciumchannel antagonist, or a TNF-1α antagonist.
 19. The topical compositionof claim 11, wherein said composition is in a form selected from thegroup consisting of: cream, lotion, gel, oil, ointment, suppository,spray, foam, liniment, aerosol, buccal and sublingual tablet or atransdermal device for absorption through the skin or mucous membranes.20. The topical composition of claim 19, wherein the composition has anointment base that makes up more than about 70% of the totalcomposition.